Self-propelling powder dispensing compositions



Ute.

States atent Ofihce 3,014,844 SELF-PROPELLING POWDER DISPENSING I COMPGSITIQNS Charles G. Thicl, Santa Monica, Irving Porush, Los Angeles, and Ronald D. Law, La Mirada, Caliti, assignors to Riker Laboratories, Inc, Los Angeics, Califl, a corporation of Delaware No Drawing. Filed Jan. 3, 1958, Ser. No. 706,908 31 Claims. (Cl. 167--82) This application is a continuation-in-part of our copending application, Serial No. 680,016, filed August 23, 1957, which is in turn a continuation-in-part of our prior application, Serial No. 637,353, filed January 31, 1957, both now abandoned.

This invention relates to self-propelling. power-dispensing compositions capable of dispensing powdered material in aerosol form and to a means for dispensing a dry powder in aerosol form having controlled particle size.

Previously it has not been possible to provide stable suspensions of powder of substantially uniform particle size in a liquified propellant for use in a pressurized container for aerosol dispensing which would not cause the closure valve, and particularly a metering valve, to

.stick. It has generally been the practice to prepare selfpropelling compositions'for aerosol administration by rendering the solid, active ingredient soluble in the liquified propellant by means of a coso-lvent. Usually the cosolvent is polar in character, e.g.,' alcohol. Unfortunately many solids, and particularly certain medicaments,

,are notfstable in polarsolvents such as water, or they are rendered unstable when in a polar solvent and incon- .tact with the metal of which the valve of a pressure-tight container is usually constructed. This is the case with epinephrine. These polar solvent-containing systems may also attack and corrode the metal valve closures of the containers and interfere with their functioning. Also,

some medicaments and other solids cannot be satisfao I torily solubilized in the usual liquified propellants, even though a cosolvent is employed. By means of-the present invention it is possible to overcome these shortcomings of the prior art and to provide simple, more stable and more satisfactory aerosol-producing compositions.

It is an object of this invention to provide a package from which a dry powder may be dispensed as an aerosol in a stream of moving gas in a controlled manner or in metered quantities.

It is a further object of the present invention to provide stable suspension compositions of powdered solids which may be dispensed effectively and efficiently in aerosol form in measured quantities, wherein the compositions remain substantially homogeneous and attractive in ap pearance during storage.

It is another object to provide stable therapeutic compositions which are self-propelling and which may be dispensed consistently in accurate doses through a metering valve for inhalation therapy without causing toxic or irritating side effects on the user.

It is an additional object of the present invention to provide stable self-propelling suspension compositions of powdered solids with reduced tendency to deposit on the container walls above the liquid level or cake out.

It is also an object to provide a method for efliciently and effectively dispensing a dry powder in aerosol form of controlled particle size in a manner which avoids sedimentation and particle agglomerization or interference PatentedDec. 26, 1961 with the functioning of the valve closure and metering mechanisms.

Other objects will be apparent to those skilled in the art from reading the following description.

The self-propelling, powder-dispensing compositions of the invention comprise a finely-divided active solid material or powder suspended in a liquified propellant, in which the solid material is substantially insoluble, and a non-ionic surface-active agent which is liquid at room temperature (65 F.), or ambient temperatures.

he finely divided powder may constitute from about 0.01 to 20% by weight of the total composition. Desirably it shall constitute from about 0.05% to 10%, and referably 0.1 to 3%, by weight of the total composition. The surface-active agent may constitute from about 0.1 to 20%, desirably between about 0.25 and 5%, and preferably, for medicinal purposes, between about 0.25 and 1%, by weight of the total composition, with the liquified propellant constituting the remainder of the composition. For, best results, the concentration of surfaceactive'agent is kept at a minimum as it may tend to solubilize the powder in the propellant, which is undesirable for reasons which will be explained below.

We have discovered that considerable deviation is permissible if the particle size of the powder is small enough. For pharmaceutical purposes the particle-size of the powder should desirablybe uniform and not greater than microns diameter, since larger particles may tend to agglomerate, separate from the suspension and may clog thevalve or orifice. of the container. Preferably the particle size should be less than 25- microns in diameter. Desirably. the. particlesize of the finely-divided solid powder should for physiological reasons be less than 25 microns and preferably less than 10 microns in diameter. For best results, the size of the particles of powder should be substantially uniform. There is no lower limit of particle size except'that'which is imposed by the use to which the aerosol produced is to be put. Where the powder is a solid medicament, the lower limit of particle size is that which will be readily absorbed and retained on or in body tissues. When particles less than one micron in diameter are administered by inhalation they tend to be re-exhaled by the patient.

Desirably the finely-divided powder should be substantially insoluble in each of the liquified propellant, the surface-active agent and in a liquified propellant-surface-active mixture. In the majority of cases wefind that solid compounds which are predominantly polar in nature by reason of a sufiicient number of polar substituent groups such as hydroxyl, amino and carboxyl groups, and salts thereof, provide most satisfactory compositions in accordance with the invention. It the powder is substantially soluble, crystal growth may occur and the particle size of the aerosolized powder when dispensed cannot be controlled. Since the compositions of the invention are intended to be used for dispensing powders in aerosol form by operating the valve of a pressuretight container charged with the compositions, it is desirable that the particle size of the suspended powder be regulated and agglomeration reduced. It is clear that if agglomeration of the powder takes place, it may tend to clog the narrow valve orifice and render the dispensing device inoperative, or it a metering valve is employed, it may be rendered inaccurate. This may lead to inaccurate dosages, which in the case of highly potent medicinals may lead to undesirable results. In addition to increasing 3 make the suspension unstable and of unsuitable appearance. In the case of powdered medicinals, adsorption in the body may be made ineffective. Consequently, it is desirable that the finely-divided powder be substantially insoluble in the other components of the compositions.

Where a finely-divided powder, such as a medicament, tends to be somewhat soluble in the mixture of surfaceactive agent and liquified propellant, it is sometimes possi- 'ble to overcome this difficulty by employing a less soluble form of the powder. For example, instead of employing the base phenylephrine, its hydrochloride may .be employed. Also, different liquified propellants may be employed in which the powder is less solubie.

Illustrative of the versatility of the compositions of the invention is the fact that the solid components may be amorphous or crystalline in nature. We prefer to use crystalline materials, as is indicated by the specific examples given below. Early efforts to produce self-propelling powder dispensing compositions showed that even to obtain compositions having only borderline properties, it was necessary to limit the solid materials employed to amorphous materials.

As will be apparent to those skilled in the art, one of the advantages of the compositions of the present invention is that they do not require the presence of a polar solvent, such as water. The compositions may be substantially anhydrous.

in carrying out the present invention, especially where water-soluble medicaments are employed, we have discovered that moisture control is important at all stages of processing. We have found that the total moisture content for finely-dispersed water-soluble medicaments should be less than 300 parts per million by weight of :total composition. This moisture control has been found to be critical to ensure thestability of the suspension during periods of storage. For instance, in the case of Example hereinbelow, when more than 300 parts per million of water are present, the medicament agglomer= ates withinone month at room temperatureanddeposits on thewalls of the container. This adversely affects the 'dose delivered, in addition to resulting in a pharmaceutically inelegant preparation, Another means of controllingand reducing the moisture content of the composition is to introduce before closing the container in which the composition is packaged, small fragments of an anhydrous, nonreactive desiccant, such as silica gel or calcium sulfate. This reduces the moisture content of the liquid phase of the composition below that which causes agglomeration. Usually 100 mgm. of desiccant is sutficien-t for a 10 ml. container charged with composition.

The solid active component to be aerosolized may be a: medicament, such as a vasoconstrictive amine or its acid-addition salts, a hormone, enzyme, alkaloid, steroid, analgesic, bronchodilator, antihistamine, antitussive, an-

ginal preparation, antibiotic and sulfona'mide and synergetic combinations of these. Examples of the medicaments which may be employed are: isoproterenol [alpha- (isopropylaminomethyl)protocatechuyl alcohol] hydro- .chloride or sulfate, phenylephrine, phenylpropanolamine,

glucagon, adrnochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, and colchicine. Others are antibiotics such as ncomycin, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline;

.adrenocorticotropic .hormone, and adrenocortical hormones, 'usch as cortisone, hydrocortisone, hydrocortisone acetate and prednisalone; insulin, etc. The active solid component may also be a cosmetic substance such as talc, an antiperspirant such as aluminum chlorohydrate,

'etc.; a polishing material such as jewelers rouge; a dye,

such as the approved food colorings; a lubricant, such as graphite and other finely-divided materials; as well as other usefulsubstances.

'4 The liquified propellant employed is one which is a gas at room temperature (65 F.) and atmospheric pressure (760 mm. of mercury), i.e., it shall have a boiling point below 65 F. at atmospheric pressure. For use in compositions intended to produce aerosols for medicinal or cosmetic use, the liquified propellant should be non-toxic. Among the suitable liquitied propellants which may be employed are the lower alkanes containing up to five carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl or propyl chlorides. The most suitable liquified propellants are the fiuorinated aand fiuorochlorinated lower alkanes such as are sold under the trademark Freon. Mixtures of the above mentioned propellants may suitably be employed.

It is contemplated that the fiuorinated or flLlOIOChiOI'b nated lower alkane shall contain not more than two carhon atoms and at least one fluorine atom. The preferred halogenated lower alkane compounds may be represented generally by the formula C H Cl F wherein Mr is an integer less than 3, n is an integer or zero, y is an integer or zero, and z is an integer, such that n-l-y+z=?.m+2. Examples of these propellants are dichlorodifluoromethane (Freon l2), dichlorotetrafiuoroethane (Freon 1 l4) CClF .CC1F trichloromonofiuoromethane (Freon 11), dichloromonofluoromethane (Freon 2l) monochloroditluoromethane (Freon 22), trichlorotrifluoroethane (Freon 113), and monochlorotrifluorm methane (Freon l3). Propellants with improved vapor pressure characteristics may be obtained by using certain mixures of these compounds, e.g., Freon 11" with Freon 12, or Freon 12" with Freon 114." For example, dichlorodifluoromethane, which has a Vapor pressure of about 70 pounds per square inch gaugeand 1,2dlCiiiO1O 1,1,2,2=tetrafluore-et nane (Freon 114"), with a vapor pressure of about 13 pounds per sqtiare inch gauge at 70 F., may be mixed in various proportions to form a propellant having an intermediate vapor pressure which is well suited for use in relatively low pressure containers.

it is most desirable that the vapor pressure of the propellant employed shall itself be Between about 25 and 65 pounds per square inch gauge at 70 F., arid prefer bly between about 30 and 40 pounds per square inch gauge at that temperature. A one-component propellant defined for use in the composition was found to give a composition with gauge pressures in the range of 55 to 65 pounds per square inch at 70 R, which are usable safely with metal containers. The two-component propellants, such as equal weight mixtures of "Freon 12 and Freon 11, were found to give gauge pressures in the range of 20 to 40 pounds per square inch at 70 R, which are usable safely with specially reinforced glass containers.

it is usually destirable to keep the gas pressure as low as possible, within the. limits imposed by the desired specific gravity of the propellant, in order to enable simple containers to be used safely and to prevent too high a pressure causing too wide a dispersal of the powder aerosol. When stronger containers, for example of stairs less steel, can be used and the active solid medicament is intended for pulmonary ingestion, it is advantageous to use a propellant with a gauge pressure of between 40 and 50 pounds per square inch; this allows complete aerosolization before the stream reaches the back of the throat. Since the powder is already present in the composition dispersed in the desired particle size, there is no need for further breakup action in the valve or applicator, so valves of simple construction may be used, and there is no need to provide special nozzles and expansion chambers, as is usually required when dispensing materials surface coating, which may even be a mono-molecular film or layer, on the finely-divided powder which prevents the particles from agglomerating either while dispersed in the propellant or when in the valve of the container.

. After an extensive investigation employing many surface-active agents, we have discovered that particular agents or combinations of them are required to give desirable results. During this investigation it was found unexpectedly that a number of surface-active agents providedv poor suspensions and failed to prevent agglomeration.

The liquid, non-ionic, surface-active agent employed should have an hydrophile-lipophile balance (HLB) ratio of less than 10. The HLB ratio is an empirical number which provides a guide to the surface-active properties of a surface-active agent. The lower the HLB ratio, the more lipophilic is the agent, and conversely, the higher the HLB ratio, the more hydrophiiic is the agent. The HLB ratio is well known and understood by the colloid chemist and its method of determination is described by W. C. Grifiin in the Journal of the Society of Cosmetic Chemists, vol. 1, No. 5, pages 311-326 (1949). Preferably the surface-active agent employed should have an HLB ratio of about 1 to 5. It is possible to employ surface-active agents which themselves do not possess an HLB ratio within these ranges, providing they are used in conjunction with other surface-active agents which have an HLB ratio which will provide a mixture having an HLB ratio within the prescribed range.

Surface-active agents which are solids at room temperature have been tried but appear to be unacceptable generally due to clogging of the valve and adapter orifices .on delivery. Lubricants for the valve, such as calcium stearate, which is without surfactant properties, were not found to be satisfactory, because they do not help to keep the powdered medicament uniformly dispersed in the pro pellant.

Those surface-active agents which are soluble or dispersible in the propellant are effective. The more propellant-soluble surface-active agents are the most effective.

For medicinal use it is also important that the surfaceactive agent should be non-irritating and non-toxic.

We have found that among the liquid non-ionic surfaceactive agents which may be employed in our compositions are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octoic, lauric, palmitic, stearic, linoleic, linolenic, eleostearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the trademark Spans") and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides may be employed. The preferred surface-active agents are the oleates of sorbitan, e.g., those sold under the trademarks Arlacel C (Sorbitan sesquioleate), Span 80 (sorbitan monooleate) and Span 85 (sorbitan trioleate).

Specific examples of other surface-active agents which may be employed are Sorbitan monolaurate V Polyoxyethylene sorbitol tetraoleate Polyoxyethylene sorbitol pentaoleate Indicative of the specificity of the surface-active agent in the compositions of the invention, there is reported below the results obtained with surface-active agents falling outside of the scope of the present invention and certain lubricants. These results are based upon tests employing the surface-active agent or lubricant in a concentration of 0.5% with a suspension of 0.5% of hydrocortisone acetate in a Freon mixture consisting of 30% Freon 11 and 70% of a mixture (Freon W) containing 61.5% Freon 114 and 38.5% Freon l2. Hydrocortisone acetate was used because it is one of the more easily suspended materials.

Compound Tested Results Paraffin Wax Stearic Acid Starry] Alcohol (solid). Beeswax Petrolatum Oleyl Alcohol (liquid) Pol yet hylene Glycol 300 Mineral Oil lsopropyl in yrist-nte Deposits as a solid in the adapter leading from the discharge valve and impairs delivery. Non- ,hornogeneous suspension. Lubricates valve.

Same as for paratlin wax.

. Same as for paraflin wax.

MYRJ 45" (Polyoxyethylene Very good suspension, elumpy, stearate). sticks to container, breaks very rapidly, lubrieates valve. Bi-i" (Poiyoxyctliylenelauryl Very poor suspension, clumpy,

alcohol). lubricntes valve. Tween 81 (Poiyoxyethylene Very poor suspension, elumpy,

sorbltnn mono-oleate). lubricates valve.

We have further discovered that in the case of compositions of the invention employing certain finely-divided powders there is a tendency to form a layer of powder at the surface of the propellant in the container and that these layers tend to deposit or cake" powdered material on the container walls above the liquid level. This has been found to occur only with those powders which have a specific gravity less than that of the propellant.

This tendency to deposit or cake out" is a serious disadvantage in that (1) such powder deposited on the container walls is not dispensed from the container, (2) the dose delivered is not correct and becomes progressively less as the amount left in the container becomes smaller and (3) in a transparent container the appearance of the product is impaired. The greater the difference in specific gravity between the powder and the propellant, the more pronounced in this tendency. By means of the present invention, it is possible to overcome these drawbacks and to provide more stable, uniform, attractive and satisfactory aerosol-producing compositions.

In some cases the undesirable deposition or caking which results where the specific gravity of the finely divided powder is substantially less than that of the propellant can be overcome by lowering the specific gravity of the liquid phase, for example by using a propellant of lower specific gravity, such as butane, or by increasing the specific gravity of the solid active powder component, for example in the case of phenylephrine by using the bitartrate salt instead of hydrochloride. In many cases, however, it is not possible to find a suitable alternative form of the active material. In such cases we have discovered, surprisingly, that the introduction of a sufficient quantity of an additional auxiliary finely divided solid of density greater than that of the liquid phase, will prevent the surface spread of lighter powders, thus avoiding caking out and the associated, above-mentioned drawbacks.

The nature of such an auxiliary solid may be of any chemical type, provided that it is compatible with the other ingredients and insoluble in the propellant. For example, we may use an inorganic compound such as sodium sulfate, calcium chloride or sodium chloride. We may also use an organic material such as powdered lactose, sucrose, epinephrine bitartrate, neomycin sulfate, or graphite. The auxiliary solid, when used in medicinal and cosmetic preparations, should be non-toxic and nonirritant. In all cases it should be without deleterious effect on the properties of the dispensed product or on the user. The particle size of the auxiliary solid should pp in this suitable for inhalation therapy.

.p =sp. gr. of auxiliary solid Pp=SP. gr. of propellant =sp. gr. of total powder constituents (auxiliary solid and active constituent) =sp. gr. of active constituent a=wt. of auxiliary solids p=wt. of propellant q='wt. of total powder constituents u=wt. of active constituent It is apparent that q=u plus a (1) To prevent surface deposit or caking the fol-lowing condition must exist:

p minus pp must not be less than zero (2) This condition is satisfied when:

PU is equal to or greater than pp (3) thus when q equals 11, equals zero. less than [312, the following exists:

u-l-a Pu PA But when p is I For a theoretical minimum, condition 2 becomes:

[7Q minus PP=ZCIO or p =p information to Equation 4, then:

( una -Px+ -Pu P thus:

uxin.

In terms of the above defined symbols, when P0 is equal to or greater than pp, a satisfactory composition is obtained whereby no surface deposit or caking of powder is obtained without the employment of an auxiliary solid or powder. When p is less than Pp, the minimum amount of auxiliary solid required to prevent deposit of solid from the composition, is expressed by Equation above. We

have found that satisfactory results may be obtained when up to about ten times the minimum is employed, but we prefer to employ between a and three times a The compositions of the invention may-be used to apply measured amounts of aerosolized solid medicaments into body cavities such as the throat or nose. They also provide a means of producing aerosolized medicaments Inhalation therapy is prompt through the intimate contact with the blood through the alveolar membrance. It also enablm drugs to act directly on respiratory sites without engendering undesirable systemic effects as happens often When drugs are administered by other routes. With very volatile substances inhalation approaches intravenous therapy in rapidity of. action. It willoften avoid the necessity of parenteral injections.- Previously aerosols for this purpose have been prepared by nebulizing aqueous solutions,

for example penicillin solutions in the treatment of pneu- 8 monia. Suspensions in oil have'been suggested in the treatment of bronchial asthma, but this is 'now widely condemned by the medical profession.

In producing the compositions and packages of the invention, a container equipped with a valve is filled with a propellant containing the finely-divided powder in suspension. A container may first be charged with a weighed amount of dry powder which has been ground to a predetermined particle size, or in a slurry of powder in the cooled liquid propellant. Alternatively and preferably, the powder and the surface-active agent may be triturated or homogenized first into a uniform paste, for instance, by a pestle and mortar. This paste is then dispersed in the cooled liquefied propellant. This procedure fosters uniform wetting of the powder particles. A container may also be filled by introducing powder and propellant by the normal cold filling method, or a slurry of the powder in that component of the propellant which boils above room temperature may be placed in the container, the valve sealed in place, and the balance of the propellant may be introduced by pressure filling through the valve nozzle. On operating the valve, the powder will be dispensed in a stream of propellant, which will vaporize providing an aerosol of dry powder. Throughout the preparation of the product care is desirably exercised to minimize the absorption of moisture where the powder is water-soluble. This may be accomplished by operat-' .ing in a dehumidified atmosphere using only dry materials and equipment.

When it is necessary to employ an auxiliary solid or powder to prevent surface deposit or caking, it is desirably introduced into the composition at the time that powdered of the appended claims. In the examples which follow,

the process described above was employed. In the examples which follow and throughout the specification, the quantities of material are expressed in terms of percentages by weight of the total composition, unless otherwise specified. The range of particle size specified in each example is that existing at the time of formulation. Where a constituent is described as micronized, it comprises 90% by weight of particles having a particle size range of between 1 and 5 microns. Examples 20 through 30 illustrate compositions in accordance with the invention employing an auxiliary solid to prevent surface deposit or caking.

Example 1 Percent Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 3.0 Span 85 (sorbitan trioleate) 1.0 Freon l1 (trichloromonofluoromethane) 30.0 Freon 114 (dichlorotetrafiuoroethane) 41.0 Freon 12 (dichlorodifiuoromethane) 25.0

Example 2 Gm. Trypsin, amorphous (more than 90% by weight within the particle size range of l to 10microns) 0.10

Span (sorbitan trioleate) 0.05 Propellant A 10.00

Example 3 Percent Pre dnisolone acetate, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 0.5 Span 85 (sorbitan trioleate) 0.5 Propellant B 99.0

:7 Prcpellant B consists of:

Freon 11" (trichloromoncfiuoromethane) 10.0 Freon 114 (dichlorotetrafluorcethane) 50.4 Freon 12" (dichlorctetrafluoroethanc) 31.6 Butane a; 8.0

Example 4 ACTH (adrenocorticotropin) (amorphous) (l USP units/mg.) (more than 90% by weight within the particle size range, of 1 to 20 micron's) N 1.00

Span 85 ('sorbitan trioleate)" 0.25 Freon'l'l (trichlorornonofluoromethane) 5.00 Freon (as d'efined'in Example 2) 93.75

Example *5 v v Percent ACTH (Adrenocorticotropin) (amorphous) USP units/mg.) (more than 90% by weight within the particle. size range .of l. to :20

microns) 0.25

Span 85" (sorbit-an trioleate) 0.25 Freon W (as defined in EXampIe'Z) 99.50

Insulin, amorphous (more than 90% by weight I within the particle size range of 1 to 5 microns) 0.25 Span 85 (sorbitan trioleate) 0.25 Freon W (as defined in Example 2) 99.50

' Example 7 Epinephrine, crystalline (free base) (more than 90% by weight within the particle size range of 1 to 5 microns 0.28 Span 85 (sorbitan. trioleate) 0.25 Freon 11 (trichlorornonofluorometha-ne) 5.00

. Freon W (as defined in Example 2) 94.47

Example 8 Epinephrine bitartrate, crystalline (more than 90% by weight withinthe particle size range of 1 to 5 microns) 0.50 Span 85(sorbitan trioleate) 0.50 Freon 11"'(trichloromonofluoromethane) 49.50 Freon '12 (dichlorodifluoromethane) .l- 49.50

' 10 Example 9 Isopropylarterenol hydrochloride, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 0.25 Span (sorbitan trioleate) 0.25 Freonll (trichlorornonofluoromethane) 49.75 Freon l2 (dichlorodifiuorcmethane) 49.75

Example 10 Phenylephrine hydrochloride, crystal-line (more than by weight within the particle size range of l to 25 microns) 0.25 Ncomycin sulfate 0.11 Hydrowrtisone 0.04 Span S5" (sorbitan trioleate) 0.25 Freon ll (trichloromonofiuoromethane) 49.675 Freon l2 (dichlorodifluorornethane) 49.675

Example 11 Neomycin sulfate, crystalline (more than 90% by weight within the particle size range of l to 25 microns) 0.50 "Span'SS (sorbita-n trioleate) 0.25 Freon ll (trichloromonofluorornethane) 4.75 Freon W (as defined lay-Example 2) 94.50

Example 12 Hydrocortisene acetate, crystalline (more than 90% by weight within the particle size range 'of l to 5 microns) 0.50

Surfactant 6-1087 (polyoxyethylene sorbitol hexaoleate) a, 0.50 Propcllant C 99.00

(Propellant C consists of: Freon 11 tn'chlorornoncflu'oromethane) 30.00% and Freon W (as defined in Example 2) 70.00%.)

Example 13 Percent Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Arlacel C (sorbitan sesquioleate) 0.50 Propellant C (as defined by Example 12) 99.00

Example 14 Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Span 80 (sorbitan monoleate) 0.50 Propellan-t- C (as defined-by Example 12) 99.00

Example 15 Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Span S5 (sorbitan trioleate) 0.50 Propellant C-(as defined by Example 12) 99.00

Narcotine, crystalline (more than 90% by weight within the particle size range of 1 to microns) 10.00 Span 85 (sorbitan trioleate) 1.00 Freon W (as defined by Example 2) 89.00

100.00 Example 17 "Dilaudid, crystalline (dihydrornorphinone hydrochloride) (more than 90% by weight within the particle size range of 1 to 5 microns) 0.5 Span 85 (sorbitan trioleate) 1.0 Freon 11 (trichloromonofiuoromethane) 30.0 Freon W" (as defined by Example 2) 68.5

1000 Example 18 Iron oxide (jewelers rouge) (more than 90% by weight within the particle size range of 1 to 20 microns) 1.0 Span 80 (sorbitan monooleate) 0.25 Freon l2 (dichlorodifiuoromethane) 98.75

This composition is useful for polishing optical components.

Example 19 Percent Hydrocortisone acetate, crystalline (more than 90% 'by weight within the particle size range of 1 to 5 microns) 0.5 Olive oil 0.5 Freon 11 30.0 Freon W (as defined by Example 2) 69.0

100.0 Example 20 .Phenylephrine hydrochloride (crystalline), micronized 0.25 Phenylpropanolamine hydrochloride (crystalline), micronized 0.50 'Neomycin sulfate (crystalline), micronized 0.10 Hydrocortisone (crystalline), micronized 0.04 Sodium sulfate (anhydrous), micronizcd 0.35 Span 85" (sorbitan trioleate) 0.80 Prd'pellant S 97.96

v 100.00 Propellant S consists of:

Freon l2 (dichlorodifluoromethane) 27 Freon 11" (trichloromonofluoromethane) 30 Freon 114 (dichlorotetrafluoroethane) 43 Example 21 Percent Phenylephrine hydrochloride (crystalline), micronized 0.25 qlfleomycin sulfate (crystalline), micronized 0.10 Hydrocortisone (crystalline), micronized 0.04 Calcium chloride, micronized 0.10 Span 85 (sorbitan trioleate) 0.50 Propellant S (as defined by Example 20) 99.01

' 100.00 I Example 22 Phenylephrine hydrochloride (crystalline), micronized I 0.25 Sodium chloride (crystalline), powdered 0.50 Span 85" (sorbitan trioleate) 0.75

Propel-lam S (as defined in Example 20) 12 Example 23' Phenylephrine hydrochloride (crystalline), micronized 0.25 Epinephrine bitartrate (crystalline), micromzed 0.75 Span (sorbitan trioleate) 1.0 Propellan-t S (as defined in Example 20) 98.0

100.00 Example 24 Phenylephn'ne hydrochloride (crystalline), micronized 0.25 Sucrose (crystaline), powdered 0.50 Span 85 (sorbitan trioleate) 0.75 Propellant S (as defined in Example 20) 98.5

Example 25 Phcnylephrine hydrochloride (crystalline), micronized 1.0 Neomycin sulfate (crystalline), micronized 3.0 Span 85 (sorbitan trioleate) 1.0 Propellant S (as defined by Example 20) 95.0

100.0 Example 26 Phenylephrine hydrochloride (crystalline), mi-

eronized 0.25 Graphite powder 0.25 Span 85" (sorbitan trioleate) 0.50 Propellant S (as defined by Example 20) 99.0

100.00 Example 27 Hydrocortisone acetate (crytalline), micronized 0.88 Sodium sulfate (anhydrous), micronized 0.88 Span 85 (sorbitan trioleate) 1.00 Propellant 8-2 97.24

Q 100.00 Propellant S-2 consists of:

Freon 12" (dichlorodifluoromethane) 50 Freon 11 (trichloromonofiuoromethane) 25 Freon 114 (dichlorotetrafluoroethane) 25 Example 28 Phenylephrine hydrochloride (crystalline), mi-

cronized 0.25 Lactrose, powdered 0.50 Span 85 (sorbitan trioleate) 0.75 Propellant S (-as defined by Example 20) 98.5

100.00 Example 29 Phenylephrine hydrochloride (crystalline), mi-

cronized 0.25

Neomycin sulfate (crystalline), micronized 0.08

Span 85 (sorbitan trioleate) 0.50 Sodium sulfate AR, micronized 0.10 Propellant X 99.07

100.00 Propellant X consists of:

Freon 12 (dichlorodifluoromethane) 30 Freon 11 (trichloromonofiuoromethane) 30 Freon 114 (dichlorotetrafluoroethane) 40 Example 30 Phenylephn'ne hydrochloride (c ystalline), mi-

cronized 0.25 Neomycin sulfate (crystalline), micronized 0.08 Thenylpy'ramine hydrochloride (crystalline)," micronized 0.20

100.00 15 Sodium sulfate (crystalline), micronized 0.15

Span 85 (sorbitan trioleate) 0.70 Propellant X (as defined by Example 29) 98.62

' 100.00 Example 31 Isoproterenol sulfate, crystalline, micronized 0.15 Span 85 (sorbitan trioleate) 0.50 Freon 113 (trichlorotrifiuoroethane) 0.95 Freon 11 (trichloromonofiuoromethane) 24.60 Freon 114 (dichlorotetrafluoroethane) 24.60 Freon 12 (dichlorodifiuoromethane) 49.20

' 100.00 Example 32 Phenylpropanolamine hydrochloride, crystalline,

micronized 0.49 Phenylephrine hydrochloride, crystalline, mi-

cronized 0.35 Neomycin sulfate, crystalline, micronized 0.10 Hydrocortisone, crystalline, micronized 0.04 Sodium sulfate, crystalline (anhydrous), mi-

cronized 0.35 Span 85" 1.00 Freon 113? 1.00 .Freon 11 29.03 *Freon 12 29.03 .Freon 114 38.71

100.00 Example 33 'Phenylephrine hydrochloride, crystalline, mi-

cronized 0.25 Phenylpropanolamine hydrochloride, crystalline,

micronized 0.50 Neomycin sulfate, crystalline, micronized 0.08 Methapyrilene hydrochloride, crystalline, micronized I V 0.10 Sodium sulfate, crystalline, micronized 0.35 fSpan 85 1.00 Freon 113 1.00 Freon 11 29.01 .Freonll lf 38.70 Freon 12 29.01

. Example 34 Crystalline glucagon, micronized 0.156 "Span 85- 0.468 Propellant S" (as defined by Example 20) 99.376

, Example 35 Anhydrous cyanocobalamin, crystalline, micronized 0.039 Span 85 0.25 Propellant S (as defined by Example 20) 99.711

Example 36 I Chlorotetracycline hydrochloride, crystalline, mi-

cronized 0.5 Lactose 0.5 "Span 85 "Propellant S" (as defined by Example 20) 98.0.

Example 37 Adrenochrome, crystalline, micronized 1.785 Span 85 Propellant S" (as defined by Example 20) 97.215

14 Example 38 Phenylephrine hydrochloride, crystalline, mi-

cronized 0.253 Neomycin sulfate, crystalline, micronized 0.080 Methapyrilene hydrochloride, crystalline, mi-

cronized 0.198 Anhydrous sodium sulfate, crystalline, micronized 0.150 Span 1.00 Propellant X (as defined by Example 29) 98.319

The terms and expressions which we have employed are used as terms of description and not of limitation, and we have no intention, in the use of such terms and expressions, of excluding any equivalents of the features shown and described or portions thereof, but recognize that various modifications are possible within the scope of the invention claimed.

What is claimed is:

1. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising between about 0.01% and 20% by weight of a finely-divided powder of a particle size less than about microns suspended in a liquefied propellant having a vapor pressure of at least about 13 lbs. per square inch gauge at 70 F., and between about 0.1 and 20% by Weight of a liquid, non-ionic surface-active agent having a hydrophile-lipophile balance ratio of less than about 10 and being soluble in said liquefied propellant; said finelydivided powder being substantially insoluble in the mixture of propellant and surface active agent; and when said finely-divided powder is water-soluble, said composition shall contain not more than about 300 parts per million of moisture.

2. A self-propelling, powder dispensing composition as defined by claim 1, wherein the powder has a substantially uniform particle size of less than about 25 microns.

3. A self-propelling, powder dispensing composition as defined by claim 1, wherein the surface active'agent has a hydrophile-lipophile balance ratio of between 1 and 5.

4. A self-propelling, powder dispensing composition as defined in claim 1, wherein the finely-divided powder shall constitute between about 0.05% and 10% by weight and the liquid, non-ionic surface-active agent between about 0.1% and 5% by weight of the total composition.

5. A self-propelling, powder dispensing composition as defined by claim 4, wherein the surface active agent is an ester of a polyhydroxy compound. 1

6. A self-propelling, powder dispensing composition as defined by claim 4, wherein the surface active agent is a fatty acid ester of sorbitan.

7. A self-propelling, powder dispensing composition as defined by claim 4, wherein the surface active agent is an unsaturated fatty acid ester of sorbitan.

8. A self-propelling, powder dispensing composition as defined by claim 7 wherein the surface active agent is an oleic acid ester of sorbitan.

9. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises a member selected from the class consisting of prednisalone and its esters.

10. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises a member selected from the class consisting of epinephrine and its salts.

11. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises a salt of isoproterenol.

12. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises isoproterenol sulfate.

13. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises isoproterenol hydrochloride.

14. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises a mixture of phenylephrine hydrochloride, phenylpropanolamine hydrochloride, and methapyrilene hydrochloride.

15. A self-propelling, powder dispensing composition as defined in claim 8 wherein the finely-divided powder comprises a mixture of phenylpropanolamine hydrochloride, phenylephrine hydrochloride, neomycin sulfate and hydrocortisone.

16. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder cornprises glucagon.

17. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises cyanocobalamin.

18. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely divided powder comprises chlorotetracycline hydrochloride.

1?. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises adrenochrome.

20. A self-propelling, powder dispensing pharmaceutical composition capable of providing a medicament in aerosol form suitable for inhalation therapy, comprising a liquefied non-toxic propellant having a vapor pressure of at least about 13 lbs. per square inch gauge at 70 F., between about 0.01% and 20% by weight of a finelydivided therapeutically active powdered medicament of substantially uniform particle size of less than about 100 microns suspended in said propellant, and between about 0.1% and 20% by weight of a liquid non-toxic non-ionic surface active agent having a hydrophile-lipophile balance ratio of less than about 10 and being soluble in said liquefied propellant; said finely-divided powder being substantially insoluble in the mixture of propellant and surface active agent; and when said finely-divided powder is watersoluble, said composition shall contain not more than about 300 parts per million of moisture.

21. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising a composition as defined in claim 1, wherein the specific gravity of the finely divided powder is at least as great as that of the liquefied propellant.

22. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising a composition as defined by claim 1 having "11 units by weight of a useful substance of specific gravity as a finely-divided powder and aunits by weight of an auxiliary solid substance of specific gravity p in powdered form suspended in a liquid of specific gravity pp wherein the minimum value of is expressed as follows:

a u n u 23. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the amount of :1 lies between the value of a f and 10 times a 24. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the amount of a lies between the valve of a and 3 times a 25. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 24, wherein the useful substance is a medicament and the auxiliary solid is a non-toxic powdered substance of particle size less than 25 microns.

26. A self-propelling powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22', wherein the auxiliary solid is sodium sulfate.

27. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is calcium chloride.

28. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is lactose.

29. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is sucrose.

30. A package comprising a pressure-tight container having a valve-controlled opening and containing alpharmaceutical composition capable of providing a measured dose of medicament in aerosol form suitable for inhalation therapy, comprising a composition as defined by claim 20 31. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises adrenocorticotropin.

References Cited in the file of this patent UNITED STATES PATENTS 2,594,296 Dautrebande Apr. 29, 1952 2,728,495 Eaton Dec. 27, 1955 2,782,975 Bird Feb. 26, 1957 2,959,325 Beard Nov. 8, 1960 OTHER REFERENCES Atlas Spans and Tweens, Atlas Powder Co.,

.mington, Del., 1942, pages 7, 8, 9 and 11.

Journal of The Society of Cosmetic Chemists (I.S.C.C.), vol. 7, No. 4, July 1956, pages 352 and 353.

Drug and Cosmetic Industry, vol. 79, No. 3, September 1956, pages 328 and 329.

Beard: Powder Aerosols, ties, vol. 31, No. 1, January 169.

Merck Index, 6th edition, Merck & Co., Rahway, N.J., 1952, pages 388, 389, 512, 559 and 560.

Becher: Principles of Emulsion Technology, Reinhold Publ. Co., New York (1955), pages 106-7.

Schwartz et al.: Surface Active Agents, Interscience Publ. Inc., New York, vol. 1 (1949), pages 324, 328.

Atlas Guide to Use of Sorbitol and Surfactants in Cosmetics, November 1956, pages 19 and 21.

Shephard: Proceedings of Scientific Sec. of Toilet Goods Assn., No. 22, December 1954, pages 30-31.

Soap and Chemical Special- 1955, pages 139, 141 and UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION fauna No 3,014,844 December 26, 1961 Charles G, Thiel et al.

It is hereby certified that error appears in the abo' ent requiring correction and that the said Letters Patent corrected below.

Column 2, line 46, for "a" read the line 47, before "mixture" insert agent column 3, line 68, for "usch" read such column 4, line 12, for "aand" read and column 5, line 21, for "vol." read Vol. column 6, line 56, after "of" insert the column 7, line 67, for "membrance" read membrane column 9, line 19, for "dichlorotetrafluoroethane" read dichlorodifluoromethane column 9, lines 25, 47, 57, and 67,colmma 10, lines 3, 12, 23, 33, 58, and 67, column 11, line 3, l0, 19, 40, and 68, column 12, lines 3, l0, 18, 27, 36, 47, 56, and 69, column 13, lines 6, 14, 32, 4B, 54, 62, and 70, and column 14, line 3, the word "Percent" should be inserted as a heading in the amounts set forth in the right-hand columns, each occurrence; column 12, line 50, for

"Lactrose" read Lactose column 14, line 43, column 15, lines 7 and 42,inf each occurrence, read by column 16, line 3, for "valve" read value same column line 57, for "pages 324, 328" read pages 324 through 328 Signed and sealed this 24th day of April 1962.

(SEAL) Attest:

ESTON G. JOHNSON DAVID L. LADD Attesting Officer Commissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 3,014,844 December 26, 1961 Charles G. Thiel et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 46, for "a" read the line 47, before "mixture" insert agent column 3, line 68, for "usch" read such column 4, line 12, for "aand" read and column 5, line 21, for "vol." read Vol. column 6, line 56, after "of" insert the column 7, line 67, for "membrance" read membrane column 9, line 19, for "dichlorotetrafluoroethane" read dichlorodifluoromethane column 9, lines 25, 47, 57, and 67, column 10, lines 3, 12, 23, 33, 58, and 67, column 11, line 3, 1O, 19, 40, and 68, column 12, lines 3, 1O, 18, 27, 36, 47, 56, and 69, column 13, lines 6, 14, 32,

48, 54, 62, and 70, and column 14, line 3, the word "Percent" should be inserted as a heading in the amounts set forth in the right-hand columns, each occurrence; column 12, line 50, for

I "Lactrose" read Lactose column 14, line 43, column 15, lines 7 and 42, "in," each occurrence, read by column 16, line 3, for "valve" read value same column line 57, for

"pages 324, 328" read pages 324 through 328 Signed and sealed this 24th day of April 1962.

(SEAL) Attest:

ESTON G. JOHNSON DAVID L. LADD Attesting Officer Commissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 3, 14,844 December 26, 1961 Charles G, Thiel et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below. I

Column 2, line 46, for "a" read the line 47, before "mixture" insert agent column 3, line 68, for "usch" read such column 4, line 12, for "aand" read and column 5, line 21, for "vol." read Vol. column 6, line 56, after "of" insert the column 7, line 67, for "membrance" read membrane column 9, line 19, for "dichlorotetrafluoroethane" read dichlorodifluoromethane column 9, lines 25, 47, 57, and 67, column 10, lines 3, 12, 23, 33, 58, and 67, column 11, line 3, 1O, 19, 40, and 68, column 12, lines 3, 1O, 18, 27, 36, 47, 56, and 69, column 13, lines 6, 14, 32, 48, 54, 62, and 70, and column 14, line 3, the word "Percent" should be inserted as a heading in the amounts set forth in the righthand columns, each occurrence; column l2, line 50, for

"Lactrose" read Lactose column 14, line 43, column 15, lines 7 and 42,"in," each occurrence, read by column 16, line 3, for "valve" read value same column line 57, for

"pages 324, 328" read pages 324 through 328 Signed and sealed this 24th day of April 1962.

(SEAL) Attest:

ESTON G. JOHNSON DAVID L. LADD Attesting Officer Commissioner of Patents 

1. A SELF-PROPELLING, POWEDER DISPENSING COMPOSITION CAPABLE OF PRODUCING A USEFUL SUBSTANCE IN AEROSOL FROM COMPRISING BETWEEN ABOUT 0.01% AND 20% BY WEIGHT OF A FINELY-DIVIDED POWDER OF A PARTICLE SIZE LESS THAN ABOUT 100 MICRONS SUSPENDED IN A LIQUEFIED PROPELLANT HAVING A VAPOR PRESSURE OF AT LEAST ABOUT 13 LBS. PER SQUARE INCH GAUGE AT 70*F., AND BETWEEN ABOUT 0.1 AND 20% BY WEIGHT OF A LIQUID, NON-IONIC SURFACE-ACTIVE AGENT HAVING A HYDROPHILE-LIPOPHILE BALANCE RATIO OF LESS THAN ABOUT 10 AND BEING SOLUBLE IN SAID LIQUEFIED PROPELLANT, SAID FINELYDIVIDED POWDER BEING SUBSTANTIALLY INSOLUBLE IN THE MIXTURE OF PROPELLANT AND SURFACE ACTIVE AGENT, AND WHEN SAID FINELY-DIVIDED POWDER IS WATER-SOLUBLE, SAID COMPOSITION SHALL CONTAIN NOT MORE THAN ABOUT 300 PARTS PER MILLION OF MOISTURE. 